Cannabinoid ligand-mediated glycogen depletion in astrocytes is associated with increased intracellular calcium, energy metabolism, and membrane dynamics

Fink, Katja (author), Zorec, Robert (author), Kreft, Marko (author)

Astrocytes orchestrate brain energy metabolism and respond to endocannabinoids via cannabinoid receptor type 1 (CB1R), whereas the contribution of CB2R remains uncertain. We combined live-cell Förster resonance energy transfer sensors for D-glucose and L-lactate, intracellular Ca$^{2+}$ imaging, glycogen assays, and whole-cell patch-clamp capacitance measurements to define how cannabinoid ligands shape astrocyte physiology in primary rat cultures. The CB1-selective agonist ACEA triggered rapid, transient elevations in [Ca$^{2+}$]ᵢ and metabolic readouts, whereas the CB2-biased ligands AM1241 and Gp1a produced sustained metabolic effects, including prolonged increases in intracellular D-glucose and L-lactate. AM1241 additionally evoked glycogen depletion. Ligand applications also increased membrane capacitance, consistent with enhanced exocytotic activity and altered membrane dynamics. CB1 immunoreactivity predominated over a weak CB2-like signal, and RT-qPCR detected Cnr1 but not Cnr2 transcripts under our conditions. Accordingly, we interpret AM1241/Gp1a actions as ligand-evoked effects that are predominantly CB1-linked (and/or off-target at the concentrations used). Together, these results show that cannabinoid ligands robustly remodel astrocytic energy metabolism and membrane behavior chiefly through CB1-associated pathways, highlighting a functional axis between cannabinoid signaling, Ca$^{2+}$ mobilization, glycogen remodeling, and exocytosis in astrocytes.

• Language: English
• Keywords: astrocytes, calcium signaling, cannabinoid receptors, exocytosis, glucose metabolism, lactate
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine; BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 15 str.
• Numbering: Vol. 169, iss. 12, art. e70332
• PID: 20.500.12556/RUL-178100
• UDC: 616.8
• ISSN on article: 1471-4159
• DOI: 10.1111/jnc.70332
• COBISS.SI-ID: 265140227

Note

Objavljen je popravek tega članka (gl. datoteko Priloga – Erratum): Journal of neurochemistry, 2026, vol. 170, iss. 1, art. e70370, DOI: https://doi.org/10.1111/jnc.70370.

• Publication date in RUL: 19.01.2026

Record is a part of a journal

• Title: Journal of neurochemistry
• Shortened title: J. neurochem.
• Publisher: Wiley, International Society for Neurochemistry
• ISSN: 1471-4159
• COBISS.SI-ID: 515029529

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: astrociti, kalcijevo signaliziranje, kanabinoidni receptorji, eksocitoza, presnova glukoze, laktat